1. Field of Invention
This invention relates to triphenylpropanamide compounds which are useful in treating inflammations but which do not demonstrate the side effects normally associated with other anti-inflammatory treatments such as glucocorticoids This invention also relates to methods for making and using the compounds of the invention.
2. Prior Art
Glucocorticoids are the only agents which reduce all the symptoms that are manifested in chronic adrenocortical disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, inflammatory bowel disease, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema. Glucocorticoids also reduce immunological response in organ transplants. The undesired side effects of these agents include hypertension, atherosclerosis, diabetes, hyperglycemia, bone thinning and electrolyte imbalance.
Mechanistically, glucocorticoids bind to the glucocorticoid receptor (GR) on the surface of leukocytes and the resulting glucocorticoid -GR complex migrates into the cell nucleus. There, the complex interacts with transcription factor AP-1 (activating protein-1), inhibiting its induction of genes that produce inflammatory cytokines and collagenase, thereby repressing the inflammatory process. However, the complex also activates GRE (glucocorticoid response element), a transcriptional activator of genes which are responsible for the undesirable side effects mentioned heretofore. The most desirable antiinflammatory medication would inhibit AP-1 without activating GRE.
Steroids, such as dexamethasone and prednisone have been found to exhibit potent antiinflammatory activity, but also exhibit the previously-mentioned side effects.
Heretofore, there has been no antiinflammatory agent found which does not cause side effects. Thus, new chemical agents are needed which would have the desired antiinflammatory effect without causing the side effects mentioned above.
Prior art compounds which relate to the triphenylcyclopropyl and triphenylpropyl compounds of the invention are as follows: U.S. Pat. No. 3,941,833 (Gognaco) describes certain amino derivatives of 2,2-diaryl-cyclopropane. They are described as being useful for the treatment of disorders of the cardiovascular system. They are intended for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin.
Gilbert, et al. in J. Med. Chem. 1983, 26, 693–699 report triphenylpropylidene amines and nitrites as inhibitors of prostaglandin synthetase
Blank et al. in J. Med. Chem. 1969, 12, 873–876 describe the inhibition by 2,3,3-triphenylpropylamines of the biosynthesis of aldosterone without altering deoxycorticosterone or corticosterone levels.
Schultz et al. in J. Med. Chem. 1967, 10, 717–724 describe diphenylpropanamides which are hypocholesteremic in rats and inhibit penicillin excretion in dogs
Burch et al. in Proc. Natl. Acad. Sci. USA 1991, 88, 355–359 describe fluorenyl propanamides which inhibit localized inflammatory reactions in mice.
German Patent No. 2,726,993 (Gognaco) describes 1-substituted 2,2-diphenylcydaopropanes. The patent indicates that they are useful as vasodilators and blood pressure loeIn agents. They are intendjed for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin.
Belgian patent No. BE 855689 (Hexachemie S. A. Fr.) describes 2,2-diphenylcyclopropyl methylamides with vasodilator activity.
Precigoux. et al. describe the compound 4,4′-(3Acetemido-2-phenylpropylideee) diphenol diacetate in Acta Crystallogr., Sect. C: Cryst. Struct. Commun., C41 (8), 1985, pp. 1244–1246.
Falkenstein et al. describe certain phenylaziridine compounds in “Single electro transfer versus nucleophilic ring opening in reactions of cistrns pairs of activated 2-pheytaziridines. Strong influence of nitrogen pyramid for N-benzoylaziridines.”, J. Org. Chem., 1993, 58, pp. 7377–7381.
Stamm et al. describe other aziridines in “Reactions with aziridines.53. Arene hydrides. 9. Intermediate substitution in the formation of a benzylic anion by an aromatic radical anion as observed with 1-benzoyl-2-phenylaziridine.”Chem. Ber., 1990, 123, pp. 2227–2230. Stamm et al. also described related aziridine structures in “Reductive ring opening of N-benzoylaziridine by anthracene hydride (anion of 9,10-dihydroanthracene) via base-induced fragmentation of the intermediate carbonyl adduct.” J. Org. Chem., 1989, 54, pp. 1603–1607. However, none of these publications describe the structures of this invention nor do they indicate that such compounds would be useful in treating inflammation.
Therefore, it is an object of this invention to provide one or more compounds capable of treating inflammatory diseases.
It is a further object of this invention to provide compounds capable of treating inflammatory diseases without causing side effects similar to those caused by glucocorticoids.
It is yet another object of this invention to provide a method of making compounds for treating inflammatory diseases.
Another object of this invention is to provide a method of treating inflammatory diseases in mammals by administration of the compounds of this invention.